WEEK 1:HEPATITIS VIRUSES Flashcards
State the 5 main types of hepatitis virus and their alternative names.
HAV – Hepatitis A Virus (formerly called infectious hepatitis)
HBV – Hepatitis B Virus (formerly called serum hepatitis)
HCV – Hepatitis C Virus (formerly called non-A, non-B hepatitis)
HDV – Hepatitis D Virus (delta virus)
HEV – Hepatitis E Virus(enteric non-A-non-B hepatitis)
State 8 other viruses causing hepatitis.
Yellow Fever
Epstein-Barr virus (EBV)
Cytomegalovirus (CMV)
Rubella virus
Herpes simplex virus (HSV)
Coxsackievirus B
Mumps virus
Adenovirus
According to the Baltimore classification which class do the hepatitis viruses belong?
Class I
Class II
Class III
Class IV
Class V
Class VI
Class VII
According to the Baltimore classification system, the hepatitis viruses belong to Class VII: Gapped double stranded DNA (dsDNA) viruses.
This class was added later to accommodate the gapped DNA genome of the hepatitis B virus.
The other classes of viruses are based on their nucleic acid type, strandedness, sense and replication method.
Which viruses contain DNA as its nucleic acid?
Hepatitis B
Which viruses are fecal-oral?
What does fecal -oral mean?
Hepatitis A and E
Fecal-oral means the transmission of diseases or infections from feces to the mouth.
It can happen through contaminated food, water, or objects, or through direct contact with feces or the anus.
Study the table on slides.
Describe the structure of Hepatitis B virus.
- Spherical shape
- 42nm in size
- Double shelled
- Envelope: Lipid bilayer membrane, Has HBsAg, Pre-S2 protein attached to the surface antigen, pre-S1 protein attach on pre-S2 protein.
- There is formation of small, medium, and large surface proteins depending on how many proteins are attached.
- Has an icosahedral capsid core: Made of capsomeres called HBcAg containing Polymerase enzyme and partially double stranded DNA genome, other Adna strand has gaps.
- Hepatitis E-antigen dissolved between the envelope and capsid. (HBeAg)
In what areas is HBV endemic?
HBV is endemic in Africa and Asia.
During the acute phase, infections range from asymptomatic hepatitis to icteric hepatitis, including fulminant hepatitis.
Define the terms:
1. Asymptomatic or flu-like symptoms hepatitis
- icteric hepatitis
- fulminant hepatitis.
- Fever, Diarrhea, Vomiting, nausea
- Yellowish sclera, jaundice, dark urine, Pain on RUQ of abdomen
- Liver failure / massive hepatocytes death
Outline the characteristics of hepatitis B virus (HBV) antigens (Ag) and antibodies (Ab).
Check PBL
Hepatitis B virus replicates in the cytoplasm.
True
False
False. Hepatitis B virus (HBV) replicates in the nucleus of infected liver cells, not in the cytoplasm. The virus’s genetic material is a partially double-stranded circular DNA, and to replicate, it uses the host cell’s machinery to transcribe this DNA into RNA and then reverse transcribe it back into DNA, which occurs in the nucleus of the host cell. This makes HBV replication unique compared to many other viruses, which often replicate in the cytoplasm.
HBV is transmitted through activities that involve percutaneous (i.e., puncture through the skin) or mucosal contact with infectious blood or body fluids (e.g., semen and saliva).
Outline them.
*Sex with an infected partner
*Injection-drug use that involves sharing needles, syringes, or drug-preparation equipment, tattooing, scarring
*Birth to an infected mother
*Contact with blood from or open sores on an infected person.
*Exposures to needle sticks or sharp instruments
Sharing razors, toothbrushes, and glucose monitoring equipment.
Outline clinical features of HBV.
- Damaged liver releases IL 1, 6 and TNF-a which are then transported via blood. They will stimulate the brain to release Prostaglandins which will affect the hypothalamic thermostat resulting in fever and Malaise.
- Liver releases hepatotoxins which activate CRZ hence activate the vomiting center, nerves leading to the stomach result in reverse peristalsis hence forceful ejection of the contents of the stomach (vomiting and nausea) increase bowel movement result in diarrhea.
There is a decrease in blood volume, weight loss, and decrease in electrolytes. - Increase in the UCB and the CB due to hepatocytes result in high levels of bilirubin in blood which accumulate in the sclera resulting in yellowish color(icterus) and other body parts such as the skin (jaundice).
- More UCB sent to the kidney for excretion in urine results in yellow to brown urine.
- Hepatocytes death result in low bile production hence there is low stercobilin resulting in clay-colored stools.
- Hepatomegaly result in pain in the RUQ
- There are elevated liver enzymes such as ALT, AST, ALP and GGT
- Decrease in clotting proteins affecting the clotting cascade, hence PT test shows increase Platelets.
- There is formation of immune complexes between viruses and antibodies which are deposited in different parts of the body resulting in inflammation. Arthritis, Myocarditis, pericarditis, glomerulonephritis, and vasculitis.
Serology of HBV
• Positive HBsAg: Has hepatitis B infection
• Positive HBsAb: There is immunity or vaccination.
• People who have immunity to HBV from a vaccine do not develop anti-HBc.
• HBcAb: Ongoing infection
• HBcAb IgM: Acute ongoing HBV infection
• Positive HBeAg: High replication and transmissibility.
• Positive HBeAb: Low transmission
NEGATIVE HBeAb: High transmissibility (Active carrier)
Describe 2 ways in which HBV tricks the immune system.
- A virus creates many subviral copies (Fake virus) with no genome and not infectious while the actual virus slips away from the immune system.
The anti-HbsAb is more likely to bind to the subviral particle more than the actual virus. (immune decoy). - E antigens are released along with the virus then presented on B cells MHC2 and humoral immunity. There is suppression of the cytotoxic T cells and suppression of TLRs in macrophages which results in slow clearance of the virus.
Describe the replication cycle of HBV.
- HBV fuses with the NTCP (high affinity) and Heparin sulfate (low affinity) on the surface of the cell.
- The virus is then endocytosed.
- There is fusion of the virus with the endocytosis membrane and its nucleocapsid is released into the cytoplasm.
- The capsid is uncoated, and the partially double stranded DNA of the virus enters the nucleus.
- After entering the host cell’s nucleus, reverse transcriptase completes the positive strand of the virus’s partially double-stranded relaxed circular DNA (rcDNA).
- The rcDNA is converted to covalently closed circular DNA (cccDNA) primarily by host enzymes in cell DNA repair mechanisms.
- RNA polymerase forms RNA transcripts: HBx, pgRNA, pre-s2, pre-s1, pre-core which are released into the cytoplasm.
- Reverse transcriptase attaches to the pgRNA to form DNA which will then be converted to Partially dsDNA. attach. Capsid proteins are synthesized forming Icosahedral capsid core around partially dsDNA and polymerase enzyme.
- The virus will gain envelope from the ER.
- The virus is exoticized by the Golgi complex.
- Can result in lysis of the hepatocytes.
What is seroconversion?
It is the development of specific antibodies in the blood serum because of infection or immunization.
Describe the graph for HBV natural course.
Discuss possible prognosis of HBV.
- Formation of scar tissue, necrosis, mitosis, and regeneration processes → cirrhosis and cellular dysplasia → hepatocellular carcinoma (HCC)
- Progress to Chronic: Cirrhosis, liver failure.
- Reactivation of previous HBV infection due to immunosuppression
- Infection with HDV
- Death
What hepatitis develops as a coinfection or superinfection with HBV and have the same route of infection?
Hepatitis D
Describe the structure of hepatitis D.
*Small, enveloped, circular, single-stranded,
*Negative RNA genome with 1700 nucleotides
*Is a defective virus
*Multiply in cells infected with HBV at the same time.
*When HDV buds from the surface of a liver cell it acquires an envelope consisting of 3 HBsAg: Small, medium and large.
*The HBs envelope makes the 35–37-nm virus particle infectious by attaching it to hepatic cells.
There are eight known genotypes (I to VIII).
V-VIII in west and central Africa.
*Has HDAg on the capsid. 2 isoforms: Small and large.
*Utilizes host RNA -polymerases and replicases. It does not produce its own enzymes.
*
Describe the etiology of Hepatitis D virus.
*Incomplete viral particle resembling a viroid
*Defective single-stranded RNA delta virus
*Requires the HBsAg coat of HBV for entry into host cells
How does HDV enter into the cell?
How do we diagnose HDV?
The mechanism of HDV entry is similar to HBV because it requires HBsAg for entry through the NTCP receptor.
Detection of antibody is the method for diagnosis of acute infection.
During HDV infection, IgM and IgG antibodies can be detected in the serum of infected individuals.
High titer of IgM anti-HDV strongly associated with elevated hepatitis D viremia and the severity of liver injury, more favorable course to HDV infection is found in individuals with IgG anti-HDV.
Name the only known protein encoded by HDV.
There are two types of the proteins. State them.
What is it used for?
Hepatitis Delta Antigen (HDAg) is the only known protein encoded by HDV.
*S-HDAg is required for the initiation of the viral genome replication.
*L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles.
Describe how Small and large HDAg are formed.
- ORF is acted by RNA polymerase II and forms S-HDAg which has 195 proteins. 24 kDa.
- On the 196 nucleotide the stop codon UAG is replaced UGG) on the mRNA by the ADAR 1 enzyme.
- The reading frame gets extended by 19 proteins forming L-HDAg which has 214 proteins. 27kDa.
Describe the life cycle of HDV.
- Virion attaches to hepatocyte by the help of the L-HBsAg.
- Virion enters into the cell, and it is uncoated.
- The ribonucleoprotein enters into the nucleus and forms genomic RNA.
- The genomic RNA is into the nucleus to form antigenomic RNA which forms a template for new transcripts of the circular genome.
- mRNA contains a reading frame which goes to the cytoplasm and is translated into HDAg at the ER.
- The s-HDAg are then taken back to the nucleus where they will attach to the circular RNA genome forming a Ribonucleoprotein.
7.RNP is then taken back to the cytoplasm where it will associate with L-HDAg and HBV envelope in the ER and form new viruses. - They are then exocytosized by the Golgi Apparatus.
Name the family and genus for hepatitis C virus.
Family: Flaviviridae, Genus: Hepacivirus
How many genotypes does HCV have?
7
Describe the characteristics of HCV infection.
Viral and host factors affect the disease progression rate
High HCV load in blood, genotype, and the degree of viral heterogeneity associated with more rapid progression.
Viral clearance is associated with both the development and persistence of strong HCV-specific cytotoxic T-cell and helper T-cell responses.
Being infected with one genotype does not protect against the others
Describe the structure of HCV.
Has a +ss RNA genome
Envelope: has E1 and E2 proteins and APO 1, A1, B. C and E
Nucleocapsid:
HBV has non-structural proteins. State them.
NS3, NS4A, NS4B, NS5B
Describe the life cycle of HCV.
- Entry: HCV binds to receptors on the surface of liver cells and enters the cell through endocytosis.
- Fusion and uncoating: The viral envelope fuses with the endosomal membrane and releases the viral RNA into the cytoplasm.
- Replication: The viral RNA is translated into a single polyprotein that is cleaved by host and viral proteases into structural and non-structural proteins.
The non-structural proteins form a complex that replicates the viral RNA using a negative-sense RNA intermediate.
- Assembly: The structural proteins (core, E1, and E2) associate with the lipid droplets in the cytoplasm and interact with the newly synthesized viral RNA to form nucleocapsids.
The nucleocapsids then bud into the endoplasmic reticulum and acquire a lipid envelope.
- Release: The enveloped virions are transported to the Golgi apparatus and secreted from the cell by exocytosis
Outline the receptors that HCV binds to for attachment into the cell.
CD81, SR-B1, LDL-R, EGFR, Eph A2
